Abstract
Lung hypoplasia (LH) is a serious cause of neonatal compromise, but little is known of its functional effects on the pulmonary circulation. Our aim was to characterize birth-related changes in the pulmonary circulation of newborn lambs with LH and to compare them with alterations in respiratory function. LH was induced in six ovine fetuses by the creation of a tracheo-amniotic shunt as well as amniotic fluid drainage starting at 105.6 ± 1.5 (mean ± SEM) days of gestation (term ∼147 d). At 139.9 ± 0.3 d, fetuses were exteriorized under anesthesia to implant vascular catheters and an ultrasonic flow probe around the left pulmonary artery. The lambs then were delivered and ventilated for 2 h, during which systemic and pulmonary artery pressures, left pulmonary blood flow, and measures of respiratory function were recorded. At autopsy, lungs were weighed and volume was measured at 20 cm H2O. In LH lambs, lung weight was 25% lower and respiratory system compliance was 30% lower than in controls. Mean pulmonary blood flow in LH lambs was 42% lower and pulmonary vascular resistance was 138% higher than in controls. Morphometry showed that volume density of pulmonary arteries in LH was 30% lower than in controls. We conclude that, in this LH model, changes in ventilatory indices were proportional to the change in lung size, whereas changes in the pulmonary circulation were greater than the change in lung size and were associated with reduced density of pulmonary arteries. LH severely impairs normal adaptation of the pulmonary circulation in the perinatal period.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- AaDO2:
-
alveolar-arterial difference of oxygen tension
- BW:
-
body weight
- CDH:
-
congenital diaphragmatic hernia
- Crs:
-
total respiratory system compliance
- EEP:
-
end-expiratory pressure
- Fio2:
-
fraction of inspired oxygen
- LH:
-
lung hypoplasia
- LV:
-
lung volume
- LW:
-
lung weight
- MAP:
-
mean airway pressure
- Paco2:
-
partial pressure of carbon dioxide in the arterial blood
- Pao2:
-
partial pressure of oxygen in the arterial blood
- PAP:
-
pulmonary artery pressure
- PBF:
-
pulmonary blood flow
- PIP:
-
peak inspiratory pressure
- PVR:
-
pulmonary vascular resistance
- SAP:
-
systemic artery pressure
- Va:
-
volume density of arteries in the lung (tissue and airspace)
- Vat:
-
volume density of arteries in lung tissue alone
- VEI:
-
ventilatory efficiency index
- Vt:
-
tidal volume
References
Moessinger AC, Santiago A, Paneth NS, Rey HR, Blanc WA, Driscoll JM Jr 1989 Time-trends in necropsy prevalence and birth prevalence of lung hypoplasia. Pediatr Perinat Epidemiol 3: 421–431
Knox WF, Barson AJ 1986 Pulmonary hypoplasia in a regional perinatal unit. Early Hum Dev 14: 33–42
Kilbride HW, Thibeault DW 2001 Neonatal complications of preterm premature rupture of membranes. Pathophysiology and management. Clin Perinatol 28: 761–785
Kilbride HW, Yeast J, Thibeault DW 1996 Defining limits of survival: lethal pulmonary hypoplasia after midtrimester premature rupture of membranes. Am J Obstet Gynecol 175: 675–681
Smith NP, Jesudason EC, Losty PD 2002 Congenital diaphragmatic hernia. Paediatr Respir Rev 3: 339–348
Sherer DM, Davis JM, Woods JR Jr 1990 Pulmonary hypoplasia: a review. Obstet Gynecol Surv 45: 792–803
Swischuk LE, Richardson CJ, Nichols MM, Ingman MJ 1979 Bilateral pulmonary hypoplasia in the neonate. AJR Am J Roentgenol 133: 1057–1063
Potter EL 1946 Bilateral renal agenesis. J Pediatr 29: 68–76
Perlman M, Williams J, Hirsch M 1976 Neonatal pulmonary hypoplasia after prolonged leakage of amniotic fluid. Arch Dis Child 51: 349–353
Thibeault DW, Beatty EC Jr, Hall RT, Bowen SK, O'Neill DH 1985 Neonatal pulmonary hypoplasia with premature rupture of fetal membranes and oligohydramnios. J Paediatr 107: 273–277
Dornan JC, Ritchie JW, Meban C 1984 Fetal breathing movements and lung maturation in the congenitally abnormal human fetus. J Dev Physiol 6: 367–375
Yoshimura S, Masuzaki H, Miura K, Hayashi H, Gotoh H, Ishimaru T 1997 The effects of oligohydramnios and cervical cord transection on lung growth in experimental pulmonary hypoplasia in rabbits. Am J Obstet Gynecol 177: 72–77
Collins MH, Moessinger AC, Kleinerman J, James LS, Blanc WA 1986 Morphometry of hypoplastic fetal guinea pig lungs following amniotic fluid leak. Pediatr Res 20: 955–960
Pringle KC, Turner JW, Schofield JC, Soper RT 1984 Creation and repair of diaphragmatic hernia in the fetal lamb: lung development and morphology. J Pediatr Surg 19: 131–140
Bohn D, Tamura M, Perrin D, Barker G, Rabinovitch M 1987 Ventilatory predictors of pulmonary hypoplasia in congenital diaphragmatic hernia, confirmed by morphologic assessment. J Paediatr 111: 423–431
Kitagawa M, Hislop A, Boyden EA, Reid L 1971 Lung hypoplasia in congenital diaphragmatic hernia. A quantitative study of airway, artery and alveolar development. Br J Surg 58: 342–346
Barth PJ, Ruschoff J 1992 Morphometric study on pulmonary arterial thickness in pulmonary hypoplasia. Pediatr Pathol 12: 653–663
Thibeault DW, Kilbride HK 1997 Increased acinar arterial wall muscle in preterm infants with PROM and pulmonary hypoplasia. Am J Perinatol 14: 457–460
Levin DL 1978 Morphologic analysis of the pulmonary vascular bed in congenital left-sided diaphragmatic hernia. J Pediatr 92: 805–809
Ting A, Glick PL, Wilcox DT, Holm BA, Gil J, DiMaio M 1998 Alveolar vascularization of the lung in the lamb model of congenital diaphragmatic hernia. Am J Respir Crit Care Med 157: 31–34
DiFiore JW, Fauza DO, Slavin R, Wilson JM 1995 Experimental fetal tracheal ligation and congenital diaphragmatic hernia: a pulmonary vascular morphometric analysis. J Pediatr Surg 30: 917–924
Michel RP, Cruz-Orive LM 1988 Application of the Cavalieri principle and vertical sections method to lung: estimation of volume and pleural surface area. J Microsc 150: 117–136
Joyce BJ, Louey S, Davey MG, Cock ML, Hooper SB, Harding R 2001 Compromised respiratory function in postnatal lambs after placental insufficiency and intrauterine growth restriction. Pediatr Res 50: 641–649
Notter RH, Egan EA, Kwong MS, Holm BA, Shapiro DL 1985 Lung surfactant replacement in premature lambs with extracted lipids from bovine lung lavage: effects of dose, dispersion technique, and gestational age. Pediatr Res 19: 569–577
Levin DL, Rudolph AM, Heymann MA, Phibbs RH 1976 Morphological development of the pulmonary vascular bed in fetal lambs. Circulation 53: 144–151
Alcorn D, Adamson TM, Maloney JE, Robinson PM 1980 Morphological effects of chronic bilateral phrenectomy or vagotomy in the fetal lamb lung. J Anat 130: 683–695
Fewell JE, Hislop AA, Kitterman JA, Johnson P 1983 Effect of tracheostomy on lung development in fetal lambs. J Appl Physiol 55: 1103–1108
Moessinger AC, Singh M, Donnelly DF, Haddad GG, Collins MH, James LS 1987 The effect of prolonged oligohydramnios on fetal lung development, maturation and ventilatory patterns in the newborn guinea pig. J Dev Physiol 9: 419–427
Liggins GC, Vilos GA, Campos GA, Kitterman JA, Lee CH 1981 The effect of spinal cord transection on lung development in fetal sheep. J Dev Physiol 3: 267–274
Adzick NS, Harrison MR, Glick PL, Villa RL, Finkbeiner W 1984 Experimental pulmonary hypoplasia and oligohydramnios: relative contributions of lung fluid and fetal breathing movements. J Pediatr Surg 19: 658–665
Harding R, Hooper SB, Dickson KA 1990 A mechanism leading to reduced lung expansion and lung hypoplasia in fetal sheep during oligohydramnios. Am J Obstet Gynecol 163: 1904–1913
Albuquerque CA, Smith KR, Saywers TE, Johnson C, Cock ML, Harding R 2002 Relation between oligohydramnios and spinal flexion in the human fetus. Early Hum Dev 68: 119–126
Harding R, Hooper SB 1996 Regulation of lung expansion and lung growth before birth. J Appl Physiol 81: 209–224
Wigglesworth JS, Desai R 1981 Use of DNA estimation for growth assessment in normal and hypoplastic fetal lungs. Arch Dis Child 56: 601–605
Nakamura Y, Yamamoto I, Funatsu Y, Motomura K, Fukuda S, Hashimoto T, Morimatsu M 1988 Decreased surfactant level in the lung with oligohydramnios: a morphometric and biochemical study. J Pediatr 112: 471–474
Hill AC, Adzick NS, Stevens MB, Mori H, Husseini W, Heymann MA 1994 Fetal lamb pulmonary hypoplasia: pulmonary vascular and myocardial abnormalities. Ann Thorac Surg 57: 946–951
Rudolph AM, Yuan S 1966 Response of the pulmonary vasculature to hypoxia and H+ ion concentration changes. J Clin Invest 45: 399–411
Tiktinsky MH, Morin FC 3rd 1993 Increasing oxygen tension dilates fetal pulmonary circulation via endothelium-derived relaxing factor. Am J Physiol 265: H376–H378
Fuhrman BP, Smith-Wright DL, Venkataraman S, Orr RA, Howland DF 1989 Proximal mean airway pressure: a good estimator of mean alveolar pressure during continuous positive-pressure breathing. Crit Care Med 17: 666–670
Walker AM, Ritchie BC, Adamson TM, Maloney JE 1988 Effect of changing lung liquid volume on the pulmonary circulation of fetal lambs. J Appl Physiol 64: 61–67
Fuhrman BP, Everitt J, Lock JE 1984 Cardiopulmonary effects of unilateral airway pressure changes in intact infant lambs. J Appl Physiol 56: 1439–1448
Peliowski A, Finer NN, Etches PC, Tierney AJ, Ryan CA 1995 Inhaled nitric oxide for premature infants after prolonged rupture of the membranes. J Pediatr 126: 450–453
Geary C, Whitsett J 2002 Inhaled nitric oxide for oligohydramnios-induced pulmonary hypoplasia: a report of two cases and review of the literature. J Perinatol 22: 82–85
Karamanoukian HL, Glick PL, Zayek M, Steinhorn RH, Zwass MS, Fineman JR, Morin FC 3rd 1994 Inhaled nitric oxide in congenital hypoplasia of the lung due to diaphragmatic hernia or oligohydramnios. Pediatrics 94: 715–718
Acknowledgements
We thank Valerie Zahra, Sally Gregg, Mary Hanna, Megan Probyn, and Samantha Louey for assistance in the experiments; Alex Satragno for assistance in fetal surgery; and Foula Sozo and Alison Thiel for assistance in biochemical assays.
Author information
Authors and Affiliations
Corresponding author
Additional information
eThis study was supported by the National Health and Medical Research Council of Australia.
Rights and permissions
About this article
Cite this article
Suzuki, K., Hooper, S., Cock, M. et al. Effect of Lung Hypoplasia on Birth-Related Changes in the Pulmonary Circulation in Sheep. Pediatr Res 57, 530–536 (2005). https://doi.org/10.1203/01.PDR.0000155753.67450.01
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/01.PDR.0000155753.67450.01
This article is cited by
-
Non-invasive carbon dioxide monitoring in neonates: methods, benefits, and pitfalls
Journal of Perinatology (2021)
